Most ocular medications may be administered topically to treat surface as well as intraocular disorders. This route is often preferred for the management of various pathological diseases that affect the anterior chamber of the eye, for two main reasons: (1) it is more conveniently administered and (2) provides a higher ratio of ocular to systemic drug levels. To be administered topically and to achieve the necessary patient compliance, the medication must present a good local tolerance.
Cyclosporine is a known immunosuppressant, which acts by reducing inflammatory cells such as activated lymphocytes in the conjunctiva (Kunert et al., Arch Opthalmol., 118:1489-96, 2000) or by increasing the number of mucin secreting goblet cells (Kunert et al., Arch Opthalmol., 120:330-7, 2002). Over the years, Cyclosporine A (CsA) has been evaluated for numerous potential applications in opthalmology.
New developments in the topical delivery of CsA can be divided in two general areas of research: new delivery systems, such as solutions, ointments, colloidal carriers and drug impregnated contact lenses, and chemical modifications of drugs or prodrugs.
At the present time, only one ophthalmic formulation of CsA is commercially available, which is currently marketed as Restasis®. The extensive literature on the delivery of CsA to the eye (Lallemand et al., European Journal of Pharmaceutics and Biopharmaceutics 56: 307-318, 2003; Nussenblatt et al., Am. J. Opthalmol. 112: 138-146, 1991; Masuda et al., Lancet 1: 1093-1096, 1989; Georganas et al., Clin. Rheumatol. 15: 189-192, 1996; Prummel et al., N. Engl. J. Med. 321: 1353-1359, 1989; Reinhard et al., Opthalmologe 94: 496-500, 1997) reflects the great medical interest and the pharmaco-economical aspects of this challenge. Despite a poor intraocular penetration, topical CsA has been successfully used in a variety of immune-mediated ocular surface phenomena such as vernal conjunctivitis, dry eye syndrome and the prevention of corneal allograft rejection. For example, Cross et al. reported that topical cyclosporine eye drop therapy not only improved the signs and symptoms of dry eye disease, but also resulted in high patient satisfaction, fewer patients with chronic dry eye visiting the ophthalmologist, and less ancillary drug use (Manag. Care Interface 2002; 15:44-49).
One obstacle to preparing an ophthalmic CsA formulation is that CsA cannot be prepared in formulations based on the commonly used aqueous ophthalmic vehicles because of both its hydrophobicity (log P=3.0) and its extremely low aqueous solubility at 6.6 mg/ml. Therefore, in most studies, CsA was dissolved and administered in vegetable oils. However, these media are poorly tolerated, resulting in relatively low ocular availability. Also, formulations prepared in these media have short shelf lives.
Oil-in-water emulsions are particularly useful in the delivery of lipophilic drugs. In vivo data from early studies confirmed that emulsions could be effective topical ophthalmic drug delivery systems, with a potential for sustained drug release.
The product currently on the market, Restasis®, is packaged in single unit doses to avoid microbial contamination because it does not contain any preservatives. It would be highly desired to have a preparation to be dispensed in a multi-dose container.
Therefore, there is a need for an ideal topical ocular formulation of CsA, which fulfills several requirements: (1) the formulation must be well tolerated, or non-irritating to the eye, (2) the formulation must be easy to administer, (3) the formulation ideally has an increased CsA residence time in the eye, (4) systemic absorption of the formulation should be avoided because the toxic CsA concentration in blood is above 300 ng/ml, (5) the formulation should have a long shelf life, and (6) the formulation should be easily manufactured.
The present invention satisfies the needs in the field by providing stable, non-irritating emulsion formulations of CsA suitable for ophthalmic application, and methods for preparing and using the formulations.